Even though the health risks and societal costs of cigarette smoking are well-known, roughly 19.8% of American adults continue to smoke. While most smokers endorse a desire to quit, very few (< 5%) will actually quit in a given year without treatment, and only about 20-25% achieve abstinence after 6 months or more of effective treatment. Therefore, there continues to be a vital need to improve outcomes for cigarette smokers seeking treatment. Current first-line medications for Tobacco Dependence include nicotine replacement therapies (such as the patch, gum, lozenge, nasal spray, and inhaler), varenicline HCl (Chantix), and bupropion HCl (Zyban), with the current standard of care in most treatment settings being to choose specific medications based primarily on availability, ease of use, and patient preference. The goal of the proposed research is to improve the delivery of smoking cessation treatment by determining if pre-treatment 1422* nicotinic acetylcholine receptor (nAChR) density in cigarette smokers is associated with smoking cessation outcome with the standard nicotine patch taper. Pilot data from our ongoing studies using positron emission tomography (PET) and the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA) in cigarette smokers indicate that the severity of up-regulation of 1422* nAChRs predicts who will be more or less likely to respond to treatment with the nicotine patch, and that this relationship between 1422* nAChR up-regulation and treatment outcome is more specific for nicotine patch treatment than for other smoking cessation treatments which are not linked as clearly with 1422* nAChR occupancy (e.g., bupropion HCl and group psychotherapy). The proposed study builds upon several ongoing lines of research. First, the 2-FA PET method to be used here was recently developed and refined by our group and close collaborators, and these refinements allow for improved precision in determining brain 1422* nAChR density in smokers than was previously possible. Second, both functional brain imaging studies of humans and post-mortem studies of human brain tissue demonstrate up-regulation of 1422* nAChRs in cigarette smokers compared to non-smoking controls, and the pilot data for this study indicates that the severity of this up-regulation is associated with response to nicotine replacement therapy. Third, the nicotine patch taper continues to be widely used. And fourth, clinical features and general measures of brain function (e.g., brain activity) have been used to predict treatment outcomes in Tobacco Dependence and other neuropsychiatric conditions; however, to our knowledge, there are no published reports linking the density of a specific brain receptor (1422* nAChRs) with treatment outcome for a medication that affects that receptor. For the proposed study, tobacco dependent cigarette smokers (n = 148; 10 to 30 cigarettes per day) will be recruited through newspaper and internet advertisements. Participants will undergo telephone and in-person screening, followed within one week by a 2-FA PET scanning session. For this PET session, a bolus of 2-FA will be injected over 1 minute and 2-FA will be infused for the remainder of the session. After 3 h (the amount of time needed for the radiotracer to reach an approximate steady state in the brain), participants will undergo 1 h of PET scanning. They will then be taken out of the scanner and will smoke to satiety (2 to 3 cigarettes). Participants will then be scanned an additional 3.5 h, so that both specific and non-displaceable 2-FA binding can be determined in regions of interest (ROIs) (e.g., thalamus, brainstem, and cerebellum). A structural magnetic resonance image of the brain will be obtained within one week of the PET session to aid in localization of ROIs on PET. Participants will then be randomly assigned to a 10-week course of treatment with either an active nicotine or matching placebo patch taper. Smoking status will be assessed at each weekly treatment visit and at the end of treatment using participant reports, exhaled carbon monoxide levels, and urinary cotinine levels. Pre-treatment 1422* nAChR density in the ROIs will be linked with treatment outcome (e.g., quit status) and other variables for the treatment groups (nicotine and placebo patch) separately and for the total group. Additionally, we will explore whether the combination of information from the PET images and rating scales can be used to identify even more robustly who will quit smoking with nicotine patch treatment.